Cancer genomic medicine in Japan and the roles of pharmacists.

Cancer genomic medicine (CGM) is a medical service that provides optimized treatment for each patient based on genes, biomarkers, environment, and lifestyle. In Japan, the approval of designed core hospitals for CGM started in 2017. In June 2019, two types of cancer gene panel tests became available in the national health insurance system, and CGM was socially implemented. While CGM is still in its infancy and there are some issues that need to be resolved, there are cases where the treatment has shown dramatic results. The present review highlights the CGM system in Japan, the issues it faces, and the role of pharmacists in this system.

Significant decreases in blood propofol concentrations during adrenalectomy for phaeochromocytoma.

AIM: The kinetics of propofol are influenced by cardiac output. The aim of this study was to examine changes in blood propofol concentrations during phaeochromocytoma surgery using target-controlled infusion (TCI) anaesthesia with propofol. METHODS: This is a prospective observational study. Ten patients with phaeochromocytoma who underwent unilateral adrenalectomy were included. Cardiac output was measured using an arterial pressure-based cardiac output analysis method. The target blood propofol concentrations were adjusted to maintain an approximate bispectral index (BIS) value of 40 before initiating surgery. The settings remained constant during surgery. Blood samples for propofol concentrations were collected from the radial artery at seven time points: two before tumour manipulation (T1, 2), two during tumour manipulation (T3, 4), and three after tumour vein ligation (T4-7). BIS values, the arterial pressure cardiac index (APCI) and haemodynamic parameters were measured at the same time points as the blood samples. The prop-ratio was calculated by dividing blood propofol concentrations by target concentrations of TCI. RESULTS: APCI increased during tumour manipulation and after tumour vein ligation. The prop-ratio was reduced significantly by approximately 40% and showed a significant negative correlation with APCI. BIS values increased significantly and showed a significant negative correlation with the prop-ratio. CONCLUSION: The increased APCI during tumour manipulation and after tumour vein ligation was associated with markedly reduced blood propofol concentrations. These results reveal that significant decreases in the anaesthetic effect may be observed in patients undergoing phaeochromocytoma surgery even if TCI anaesthesia is used with propofol.

Sex Differences in the Blood Concentration of Tacrolimus in Systemic Lupus Erythematosus and Rheumatoid Arthritis Patients with CYP3A5*3/*3.

The purpose of this study was to describe the impact of sex and cytochrome P450 3A5 (CYP3A5) variant on the blood concentration of tacrolimus in patients with systemic lupus erythematosus or rheumatoid arthritis. The blood concentration of tacrolimus (ng/mL) divided by the daily dose of tacrolimus (mg/day) and the patient's weight (kg) (C/D) was obtained from 55 patients. The C/D value was analysed according to genetic variation in CYP3A5 or ATP binding cassette subfamily B member 1 (ABCB1), sex, and age. The C/D value in the CYP3A5*3/*3 group was significantly higher than in the CYP3A5*1/*1 and *1/*3 groups (p < 0.05, effect size: d = 1.40). In the CYP3A5*3/*3 group, the concentration of tacrolimus was significantly higher in men than in women (p < 0.05, effect size: d = 1.78). Furthermore, in the CYP3A5*3/*3 group, the concentration of tacrolimus was significantly higher in women aged over 50 years than in women aged under 50 years (p < 0.05, effect size: d = 1.18). In contrast, ABCB1 genetic variations did not show any significant effect on the C/D value. Since the blood concentration of tacrolimus in patients with CYP3A5*3/*3 varies depending on sex and age, these factors should be considered when studying the difference of sex in CYP3A.

Quantitative evaluation of biliary elimination of gadoxetate, a magnetic resonance imaging contrast agent, via geometrical isomer-specific transporting system in rats.

Gadoxetate, a magnetic resonance imaging contrast agent, is eliminated into bile. Gadoxetate geometrical isomers are chromatographically classified into two groups by differences between their ionic states (GIs-I and GIs-II; 65:35 w/w); however, the elimination mechanism of each isomer in vivo remains controversial. Thus, the contribution of carrier-mediated transport systems on the biliary elimination of gadoxetate was examined. Gadoxetate was injected intravenously into rats, and the time courses of the plasma concentrations and biliary elimination of GIs-I and GIs-II were examined by high-performance liquid chromatography techniques. The results showed that 34.7% of GIs-I (GIs-I(s); 22.6% of gadoxetate) was quickly eliminated into bile within 30 min after injection. The contents of the residual GIs-I (GIs-I(r)) and GIs-II in plasma similarly decreased according to a first-order elimination process (t1/2=23-27 min), and 64.0% of GIs-I(r) and GIs-II (49.6% of gadoxetate) was eliminated into the bile within 2 h after injection. There was no significant difference between the elimination half-lives of GIs-I(r) and GIs-II in rats. In conclusion, the geometrical isomer with specific conformation corresponding to 22.6% of gadoxetate was eliminated into bile in rats via a carrier-mediated transport system no later than 30 min after intravenous injection.

Using the Natural Language Processing System Medical Named Entity Recognition-Japanese to Analyze Pharmaceutical Care Records: Natural Language Processing Analysis.

BACKGROUND: Large language models have propelled recent advances in artificial intelligence technology, facilitating the extraction of medical information from unstructured data such as medical records. Although named entity recognition (NER) is used to extract data from physicians' records, it has yet to be widely applied to pharmaceutical care records. OBJECTIVE: In this study, we aimed to investigate the feasibility of automatic extraction of the information regarding patients' diseases and symptoms from pharmaceutical care records. The verification was performed using Medical Named Entity Recognition-Japanese (MedNER-J), a Japanese disease-extraction system designed for physicians' records. METHODS: MedNER-J was applied to subjective, objective, assessment, and plan data from the care records of 49 patients who received cefazolin sodium injection at Keio University Hospital between April 2018 and March 2019. The performance of MedNER-J was evaluated in terms of precision, recall, and F1-score. RESULTS: The F1-scores of NER for subjective, objective, assessment, and plan data were 0.46, 0.70, 0.76, and 0.35, respectively. In NER and positive-negative classification, the F1-scores were 0.28, 0.39, 0.64, and 0.077, respectively. The F1-scores of NER for objective (0.70) and assessment data (0.76) were higher than those for subjective and plan data, which supported the superiority of NER performance for objective and assessment data. This might be because objective and assessment data contained many technical terms, similar to the training data for MedNER-J. Meanwhile, the F1-score of NER and positive-negative classification was high for assessment data alone (F1-score=0.64), which was attributed to the similarity of its description format and contents to those of the training data. CONCLUSIONS: MedNER-J successfully read pharmaceutical care records and showed the best performance for assessment data. However, challenges remain in analyzing records other than assessment data. Therefore, it will be necessary to reinforce the training data for subjective data in order to apply the system to pharmaceutical care records.

Prognostic Model of Baseline Medications plus Neutrophil-to-lymphocyte Ratio in Patients with Advanced Non-small-cell Lung Cancer Receiving Immune Checkpoint Inhibitor plus Platinum Doublet: A Multicenter Retrospective Study.

Background: Association between baseline medications plus neutrophil-to-lymphocyte ratio (NLR) and the effectiveness of immune checkpoint inhibitor (ICI) plus platinum doublet remains unknown, despite several reported prognostic models. We used real-world data to investigate whether baseline medications plus NLR predict survival outcomes in patients with advanced non-small-cell lung cancer (NSCLC) receiving ICI plus platinum doublet. Methods: This multicenter, retrospective, observational study conducted in Japan between December 2018 and March 2021 used real-world data of consecutive patients with advanced NSCLC who received ICI (pembrolizumab or atezolizumab) plus platinum doublet as first-line treatment. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The prognostic score for baseline medications plus NLR was weighted by regression ß coefficients and used to categorize patients into good, intermediate, and poor prognoses groups. In addition, time-dependent receiver operating characteristic curve analyses and univariable and multivariable Cox proportional hazards models were constructed. Results: Overall, 241 patients were included. Poor prognosis was significantly associated with worse PFS (hazard ratio [HR]: 1.78; 95% confidence interval [CI]: 1.08-2.94; P = 0.025) and OS (HR: 3.59; 95% CI: 2.05-6.28; P < 0.001) than good prognosis. Harrell's C-index for this prognostic model was 0.648. Conclusions: Baseline medication plus NLR could predict progressively worse survival outcomes in patients with advanced NSCLC receiving ICI plus platinum doublet and could be used as a prognostic index for poor outcomes.

Influence of hemodynamic variations on the pharmacokinetics of landiolol in patients undergoing cardiovascular surgery.

Although landiolol is useful in the emergency management of atrial fibrillation, atrial flutter, and tachycardia, as well as in perioperative arrhythmia control, the influence of hemodynamic changes on the pharmacokinetics of landiolol is unknown. We investigated the influence of hemodynamic variation and the following hepatocirculatory changes after systemic heparinization on the pharmacokinetics of landiolol in patients undergoing cardiovascular surgery under cardiopulmonary bypass. Cardiac output and cardiac index (CI) were continuously monitored in 19 patients using an arterial pressure-based cardiac output monitor. The middle and right hepatic venous blood flow indexes (mHVBFI and rHVBFI) were measured by transesophageal echocardiography, and hemodynamic data were collected at points (T1-T3) as follows: T1, before administration of heparin and after sternotomy; T2, just before systemic heparinization (300 U/kg); T3, 10 min after T2. The plasma concentration of landiolol was measured by HPLC at the same point. After administration of heparin, mean arterial blood pressure, CI, mHVBFI, and rHVBFI were significantly decreased (<0.05). Heart rate was not significantly changed. After systemic heparinization, the landiolol concentration was significantly decreased from 0.407±0.251 µg·mL(-1) to 0.232±0.207 µg·mL(-1) (<0.01). There was no significant difference between T1 and T2 (=0.88). In conclusion, the plasma concentration of landiolol was decreased by diminished CI due to systemic heparinization, but not affected by the change of hepatic blood flow.

Chromatography columns packed with thermoresponsive-cationic-polymer-modified beads for therapeutic drug monitoring.

Therapeutic drug monitoring, which is used to determine appropriate drug doses, is critical in pharmacological therapy. In this study, we developed thermoresponsive chromatography columns with various cationic properties for effective therapeutic drug monitoring. Thermoresponsive cationic copolymer poly(N-isopropylacrylamide-co-n-butyl methacrylate-co-N,N-dimethylaminopropyl acrylamide) (P(NIPAAm-co-BMA-co-DMAPAAm))-modified silica beads, which were used as the chromatographic stationary phase, were prepared by modifying the radical initiator of the silica beads, followed by radical polymerization. Characterization of the prepared silica beads demonstrated that thermoresponsive polymers with various cationic properties successfully modified the beads. The elution behavior of several steroids in the prepared bead-packed columns at various temperatures indicated that the optimal column operating temperature was 30 °C. Appropriate measurement conditions for 13 drugs were investigated by varying the cationic properties of the columns and the pH of the mobile phase. Drug concentrations in serum samples were determined using the developed columns and mobile phases with a suitable pH. Voriconazole concentrations in human serum samples were determined using the developed columns with all-aqueous mobile phases. We anticipate that the developed chromatography columns can be used for therapeutic drug monitoring because drug concentrations can be measured using all-aqueous mobile phases that are suitable in clinical settings.

Effect of a lever aid on hand strength required for using a handheld inhaler correctly.

In the treatment of asthma and chronic obstructive pulmonary disease, using a lever aid to improve drug delivery from an inhaler is recommended for patients with poor muscle strength. However, no studies have investigated the effect on hand strength of using a lever aid. Here, we measured hand strength before and after operating a lever aid and tried to predict the required strength. We compared the pinch force required to activate a pressurized metered dose inhaler (pMDI) and a dry powder inhaler as well as the rotational torque required to activate a soft mist inhaler (SMI) before and after attaching a lever aid. We then assessed the correlation between the theoretical and measured pinch force after fitting the lever aid. Use of the lever aid significantly reduced the pinch force required for pMDI operation from 26.13-48.74 N to 4.90-16.87 N. In contrast, using a lever aid significantly reduced the force needed to rotate SMI, although the rotational torque required to operate did not change. There was a significant positive correlation between the theoretical and measured pinch forces required to activate a pMDI fitted with a lever aid. Using a lever aid will increase the number of patients who can use this device.

Lorlatinib-induced visual and auditory hallucinations: A case report.

Lorlatinib can cause visual and auditory hallucinations. And, it is necessary to keep in mind that hallucinations can persist even after discontinuation in patients who develop hallucinations while receiving lorlatinib.

Peripheral blood biomarkers predict immune-related adverse events in non-small cell lung cancer patients treated with pembrolizumab: a multicenter retrospective study.

Background: Pembrolizumab is currently the standard treatment for patients with advanced non-small cell lung cancer (NSCLC). However, the association between immune-related adverse events (irAEs) and peripheral blood cell counts remains unclear. We aimed at identifying peripheral blood cell counts that may predict the development of pembrolizumab-induced irAEs. Methods: We retrospectively analyzed data on consecutive patients with advanced NSCLC who received pembrolizumab monotherapy as first-line or later-line therapy at the National Cancer Center Hospital and Keio University Hospital. We used data between December 2015 and November 2018. The primary endpoint was the relationship between peripheral blood cell count data and early-onset irAEs during the 6-weeks study period. Receiver operating characteristic (ROC) curve and multivariable logistic regression analyses were performed. Results: In total, 92 patients were evaluated, of whom 45 (48.9%) had at least one irAE during the first 6-weeks after treatment initiation. The ROC curves revealed that the optimal cutoff of pretreatment absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) for onset of irAEs were 1459, 2.320, 1.538, and 165, respectively. Multivariable logistic regression analyses revealed that pretreatment ALC>1450 and LMR>1.6 were significantly associated with a reduced risk for onset of any irAEs, whereas pretreatment NLR>2.3 and PLR>165 were significantly associated with an increased risk. Conclusions: The findings suggest that considering the routine availability of blood cell count data before the initiation of treatment with pembrolizumab, it may be useful in identifying early-onset irAEs during the 6-weeks study period in clinical practice.

Absolute Lymphocyte Count Predicts Immune-Related Adverse Events in Patients With Non-Small-Cell Lung Cancer Treated With Nivolumab Monotherapy: A Multicenter Retrospective Study.

BACKGROUND: Among patients with advanced non-small-cell lung cancer who were treated with nivolumab monotherapy, the association of peripheral blood count data (at baseline and 2 weeks after treatment initiation) with the early onset of immune-related adverse events (irAEs) and treatment efficacy has not been clearly established. This study aimed to identify peripheral blood count data that may be predictive of the development of nivolumab-induced irAEs in a real-world clinical setting. MATERIALS AND METHODS: This multicenter observational study retrospectively evaluated consecutive patients with advanced non-small-cell lung cancer undergoing nivolumab monotherapy in the second- or later-line setting between December 2015 and November 2018 at the National Cancer Center Hospital and Keio University Hospital in Japan. The primary endpoint was the association between peripheral blood count data and irAEs during the 6-week study period. Receiver operating characteristic curve and multivariable logistic regression analyses were performed. RESULTS: Of the 171 patients evaluated, 73 (42.7%) had ≥1 irAE during the first 6 weeks following treatment initiation. The median time to irAEs from the initiation of nivolumab was 15 (interquartile range: 13-28) days. Receiver operating characteristic curve analyses revealed that the optimal cut-off values of the absolute lymphocyte count, neutrophil-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio 2 weeks after treatment initiation for early irAE onset were 820, 4.3, and 2.2, respectively. In multivariable logistic regression analyses, absolute lymphocyte count >820 at 2 weeks after treatment initiation was significantly associated with an increased risk of early onset of any irAE. In contrast, no significant association was observed for the neutrophil-to-lymphocyte ratio (>4.3) or the lymphocyte-to-monocyte ratio (>2.2) at 2 weeks following treatment initiation. CONCLUSIONS: The absolute lymphocyte count >820 at 2 weeks following nivolumab initiation predicts early onset of irAEs during a 6-week study period. Routinely available absolute lymphocyte count, which is measured after the initiation of nivolumab, may be useful for identifying patients at risk of early onset of irAEs.

Formulation Development of Mucoadhesive Microparticle-Laden Gels for Oral Mucositis: An In Vitro and In Vivo Study.

In order to relieve pain due to oral mucositis, we attempted to develop mucoadhesive microparticles containing indomethacin (IM) and gel preparations with IM microparticles that can be applied to the oral cavity. The mucoadhesive microparticles were prepared with a simple composition consisting of IM and polyvinyl alcohol (PVA). Two kinds of PVA with different block properties were used, and microparticles were prepared by heating-filtration and mixing-drying. From the X-ray powder diffraction patterns, differential scanning calorimetry thermograms, and morphological features of the IM microparticles, IM should exist as polymorphic forms in the microparticles. Rapid drug release properties were observed in the IM microparticles. Increased drug retention was observed in IM microparticles containing PVA, and the IM-NK(50) gel, using a common block character PVA and heating-filtration, showed good long-term drug retention properties. In vivo experiments showing significantly higher drug concentrations in the oral mucosa were observed with IM microparticles prepared by heating-filtration, and the IM-NK(50) gel maintained significantly higher drug concentrations in the oral mucosa. From these results, the IM-NK(50) gel may be useful as a preparation for relieving oral mucositis pain.

Rapid single-nucleotide polymorphism detection of cytochrome P450 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genes for the warfarin dose adjustment by the SMart-amplification process version 2.

BACKGROUND: Polymorphisms of the CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) gene (CYP2C9*2, CYP2C9*3) and the VKORC1 (vitamin K epoxide reductase complex, subunit 1) gene (-1639G>A) greatly impact the maintenance dose for the drug warfarin. Prescreening patients for their genotypes before prescribing the drug facilitates a faster individualized determination of the proper maintenance dose, minimizing the risk for adverse reaction and reoccurrence of thromboembolic episodes. With current methodologies, therapy can be delayed by several hours to 1 day if genotyping is to determine the loading dose. A simpler and more rapid genotyping method is required. METHODS: We developed a single-nucleotide polymorphism (SNP)-detection assay based on the SMart Amplification Process version 2 (SMAP 2) to analyze CYP2C9*2, CYP2C9*3, and VKORC1 -1639G>A polymorphisms. Blood from consenting participants was used directly in a closed-tube real-time assay without DNA purification to obtain results within 1 h after blood collection. RESULTS: We analyzed 125 blood samples by both SMAP 2 and PCR-RFLP methods. The results showed perfect concordance. CONCLUSIONS: The results validate the accuracy of the SMAP 2 for determination of SNPs critical to personalized warfarin therapy. SMAP 2 offers speed, simplicity of sample preparation, the convenience of isothermal amplification, and assay-design flexibility, which are significant advantages over conventional genotyping technologies. In this example and other clinical scenarios in which genetic testing is required for immediate and better-informed therapeutic decisions, SMAP 2-based diagnostics have key advantages.

Effect of distal subtotal gastrectomy with preservation of the celiac branch of the vagus nerve to gastrointestinal function: an experimental study in conscious dogs.

OBJECTIVE: To evaluate the effects of distal subtotal gastrectomy with preservation of the celiac branch of the vagus nerve on gastrointestinal function. SUMMARY BACKGROUND DATA: The operative procedure of distal subtotal gastrectomy with preservation of the celiac branch of the vagus nerve is now in the spotlight in Japan with the goal of finding a function-preserving surgical technique. However, there has been no analysis of the effect of this type of surgery on gastrointestinal function. In this article, we describe the results of a fundamental experiment on distal subtotal gastrectomy with preservation of the celiac branch of the vagus nerve. METHODS: Twenty conscious dogs were divided into 2 groups, each subdivided into 2 groups of 5: a normal intact dog group (NG) divided into 2 groups, with preservation (PNG) and resection (RNG; these dogs were truncally vagotomized including transaction of the celiac branch) of the celiac branch, and a gastrectomy dog group (GG) divided into 2 groups, with preservation (PGG) and resection (RGG) of the celiac branch. The motility of the dogs was recorded using strain gauge force transducers. The effects of the preservation of the celiac branch of the vagus nerve on gastrointestinal motility, gastric emptying, and pancreatic insulin release were evaluated. RESULTS: The motility index of gastrointestinal motility with preservation of the celiac branch was higher than the motility index with resection of the celiac branch in fasted and fed of NG and GG. In gastric emptying, significant differences were found between the PNG and RNG but not between the PGG and RGG. In the fasted state for 80 minutes of the PNG and PGG, the serum insulin concentration reached a peak during the early phase III at 20 minutes in the gastric body and the antrum. CONCLUSIONS: This study has shown that it is effective to preserve the celiac branch of the vagus nerve for gastroduodenal motility, gastric emptying, and pancreatic insulin release after a gastrectomy.

[Comparison of dissolution profile and plasma concentration-time profile of the thalidomide formulations made by Japanese, Mexican and British companies].

Thalidomide is an important advance in the treatment of multiple myeloma. In Japan thalidomide is now on the approval step for the treatment of multiple myeloma. The drug has some bothersome side effects such as defect of organogenesis, neuropathy, constipation and fatigue, but is likely more effective than standard chemotherapy and is changing multiple myeloma treatment. At this moment, Japanese patients must import the thalidomide preparations from Mexico, Britain and elsewhere, but after approval, they patients will be able to get the new Japanese thalidomide capsules. In order to determine appropriate amounts of Japanese thalidomide capsules in the treatment of multiple myeloma, we compared the dissolution profile and plasma thalidomide concentrations of Japanese and British capsules and Mexican tablets. The dissolution test was performed according to the Japanese and the United States Pharmacopoeia. The pharmacokinetic data for Japanese capsules were obtained from the clinical trial in Japanese subjects and compared with those data published for other formulations. The dissolution rate of the Japanese capsule was the fastest, followed by British and Mexican formulations. The pharmacokinetic profiles of Japanese and British capsules were similar, while the 100 mg Japanese thalidomide capsule demonstrated a 1.6-fold higher maximum plasma concentration than the 200 mg Mexican thalidomide tablet (1.7 vs. 1.1 microg/ml), greatly shortened t(max) (4.5 vs. 6.2 h), and the apparent half life was only one-third of the Mexican tablet (4.8 vs. 13.5 h). A comparison of the dissolution and the pharmacokinetic absorption profiles demonstrated a rank-order correlation. Physicians and pharmacists should be aware of the probable alteration in plasma thalidomide concentration when switching to the Japanese capsule, especially from the Mexican tablet, and should monitor clinical response carefully.

Possible associations of personality traits representing harm avoidance and self-directedness with medication adherence in Japanese patients with type 2 diabetes.

BACKGROUND: Insufficient medication adherence in diabetes patients, of which numbers continue to increase globally, remains a critical issue. Medication adherence is multifactorial and determined by interactions among factors including socioeconomic status, health care team and system, condition, therapy, and patient-specific factors. On the other hand, personality traits have been studied in adherence other than to medication. Using the instruments of Temperament and Character Inventory (TCI), Harm Avoidance (TCI-HA) and Self-directedness (TCI-SD) showed distinguishing associations with adherence of health-related programs. However, few studies have been performed to elucidate psychometric properties related to medication adherence. We investigated how TCI-HA and TCI-SD of patients with diabetes are related to medication adherence. METHOD: A cross-sectional survey was conducted among type 2 diabetes patients recruited at medical institutions or via an online research company. Medication adherence was measured using the 8-item Morisky Medication Adherence Scale (MMAS-8). Personality traits were assessed using the established scales of TCI-HA and TCI-SD. Univariate and multivariate regression analyses of the MMAS-8 scores were performed in addition to assessing demographic and disease characteristics and TCI-HA and TCI-SD. RESULTS: A total of 358 responses were analyzed. Multivariate regression analysis of MMAS-8 scores revealed that higher TCI-SD was related to better adherence and experiencing drug-related side effects was related to poor adherence. Aging was significantly associated with better medication adherence in univariate regression analysis but became insignificant in multivariate regression. CONCLUSIONS: In diabetes patients, the anxiety reflected in TCI-HA tends to lower and the self-control reflected in TCI-SD tends to promote medication adherence. TCI-SD has a greater effect than TCI-HA.

Assessment of DDR2, BRAF, EGFR and KRAS mutations as therapeutic targets in non-adenocarcinoma lung cancer patients.

Molecular-targeted therapy has not been established in non-adenocarcinoma lung cancer (non-AdLC), as no targets that affect the clinical efficacy of molecular-targeted drugs have yet been identified. In this study, we investigated the frequency of genetic variations in discoidin domain receptor 2 (DDR2), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) in non-AdLC patients, in order to evaluate the possibility of genetic mutations in these genes being used as therapeutic targets for the treatment of patients with non-AdLC. For this purpose, we enrolled 150 non-AdLC patients who had undergone surgery at the Gunma University Hospital between December, 2003 and December, 2012. Genetic mutations in the EGFR, KRAS, DDR2 and BRAF genes were detected by a sequencing method or probe assay using DNA derived from cancer tissues. No somatic mutations in DDR2 or BRAF were detected in non-AdLC patients. Conversely, genetic mutations in EGFR exon 19 were found in 3 squamous cell carcinoma (SCC) and 3 adenosquamous carcinoma patients, whereas KRAS codon 12 mutations were also found in 3 SCC patients and 1 large-cell neuroendocrine carcinoma patient. EGFR and KRAS mutations were mutually exclusive. This study indicated that, although DDR2 and BRAF mutations may only rarely be used as therapeutic targets, EGFR and KRAS mutations may represent candidate therapeutic targets, at least in the non-AdLC patients investigated.

Intragastric administration of rikkunshito stimulates upper gastrointestinal motility and gastric emptying in conscious dogs.

BACKGROUND: Traditional Japanese medicine, known as Kampo medicine, consists of mixtures of several medicinal herbs widely used to treat upper gastrointestinal disorders in Japan. Rikkunshito, one of these medicines, has not been evaluated with respect to its influence on gastrointestinal motor activity. We investigated the effect of rikkunshito on upper gastrointestinal motility and plasma ghrelin concentrations in conscious dogs. METHODS: Contractile response to intragastric administration of rikkunshito was studied via surgically implanted force transducers. A powdered extract of rikkunshito (1.3, 2.7, and 4.0 g) dissolved in water was administered into the stomachs of normal and vagotomized dogs before feeding and gastric emptying was evaluated. Several inhibitors of gastrointestinal motility (atropine, hexamethonium, and ondansetron) were injected intravenously before intragastric administration of rikkunshito. Plasma acylated ghrelin levels after intragastric administration of rikkunshito were measured. RESULTS: In a fasting state, intragastric administration of rikkunshito induced phasic contractions in the duodenum and jejunum in normal dogs. Rikkunshito-induced contractions were inhibited by atropine, hexamethonium and ondansetron. In vagotomized dogs, rikkunshito induced phasic contractions, similar to normal dogs. Gastric emptying was accelerated by intragastric administration of rikkunshito in a dose-dependent manner. The plasma acylated ghrelin level 150 min after intragastric administration of 4.0 g of rikkunshito was significantly higher than the control value. CONCLUSIONS: Intragastric administration of rikkunshito stimulates gastrointestinal contractions in the interdigestive state through cholinergic neurons and 5-HT type 3 receptors. Moreover, rikkunshito increases plasma acylated ghrelin levels. Rikkunshito may alleviate gastrointestinal disorders through its prokinetic effects.